The present invention, in some embodiments thereof, relates to compositions comprising PEDF and uses of same in the treatment and prevention of ovary-related syndromes.
Unlike any other organ, the female reproductive organs (i.e., ovary, uterus, and placenta) exhibit cyclic regulation of angiogenesis [1]. In the ovary, regulation of angiogenesis is critical for achieving a healthy mature oocyte. During folliculogenesis, the primordial and primary follicles are avascular and receive nutrients and oxygen by passive diffusion from stromal blood vessels. The vascular sheath that develops around each follicle is confined to the theca cells layer, whereas the granulosa cells remain avascular until ovulation, isolated from direct blood supply by the “blood follicular barrier”. Thus, the maturing follicle remains avascular before ovulation, implying that regulatory mechanism must be present to prevent premature follicular vascularization.
Studies showed that culture media, conditioned by theca cells, stimulate proliferation and migration of endothelial cells regardless of the developmental stage of the follicle. However, Granulosa cells from early follicular phase inhibited migration and proliferation of endothelial cells, while towards ovulation, prior to becoming part of the highly vascular corpus luteum (CL) [3], they stimulated migration and proliferation of endothelial cells [4].
To date, extensive research has been performed to characterize pro-angiogenic factors in the ovary. Indeed, vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) were shown to play an important role in the regulation of ovarian angiogenesis. However, only very few studies were conducted to find follicular anti-angiogenesis factors that prevent vessels penetration during folliculogenesis [5].
Ovarian stimulation is used with the intention of retrieving a high number of oocytes in order to improve the outcome of assisted reproductive treatments. However, administration of high doses of exogenous gonadotropins may lead to ovarian hyperstimulation syndrome (OHSS). This syndrome appears to be induced by the ovarian release of vasoactive-angiogenic substances which results in vascular hyperpermeability, leakage and shift of fluids from blood vessels into the extravascular space leading to consequent clinical manifestations including ascites and edema. Since severe OHSS is potentially life-threatening, that can occur in an otherwise healthy young women undergoing fertility treatments, much effort is made to prevent this to iatrogenic complication. VEGF was recently pointed out as a crucial protein participating in the development of OHSS (reviewed in [6]) and the inhibition of the VEGF system could prevent OHSS from occurring. For example, Bevacizumab (Avastin), a humanized monoclonal antibody that recognizes and blocks vascular endothelial growth factor A was suggested as the premium treatment [7]. However, serious adverse have been reported such as bowel perforation, heart attack and stroke.
In a similar manner to the ovarian follicle, the endometrium also undergoes cyclical changes in the course of the ovulatory cycle. Angiogenesis is reinitiated in the uterus during the follicular phase and continues through the luteal phase of the menstrual cycle due to hormonal induction [1]. In both in vivo and in vitro human models, it has been demonstrated that endometrial angiogenesis is regulated by VEGF, and its expression is significantly increased by estradiol (E2) and progesterone (P) [8].
Endometriosis is a pathological condition characterized by ectopic endometrial implants, commonly in the peritoneal cavity. Active endometriosis is characterized by hypervascularization both within and surrounding the implant. A higher VEGF level has been observed in the peritoneal fluid of patients with endometriosis and its production is stimulated by both E2 and P [8].
Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, which was first described as a neurotrophic factor, able to promote and support the growth of neuronal cells [9]. However, it was later shown that besides its neurotrophic function, PEDF is also a potent, natural inhibitor of angiogenesis [10]. Importantly, its anti-angiogenic activity is far greater than that of any other known endogenous factor. The anti-angiogenic effect of PEDF has been extensively investigated in the eye, demonstrating its role in decreasing abnormal neovascularization, mainly by inhibiting the stimulatory activity of several strong pro-angiogenic factors, such as VEGF [11]. Although originally discovered in culture media of retinal pigment epithelial cells, PEDF is widely expressed throughout the body: the nervous system, ovary, uterine, liver [12] and plasma [13]. Despite the significant expression of PEDF in the reproductive system, there is only limited data about its function in the ovary [14] and uterus [15, 16] referring mainly to regulation in cancer.
U.S. Patent Application Number 20080274967 relates to the use of phosphorylated PEDF for the treatment of ovarian cancer.
U.S. Patent Application Numbers 20030216286 and 20040014664 teaches the use of PEDF for inhibiting ovarian and endometrial neovascularization such as for use as a contraceptive by attenuating neovascularization associated with ovulation, implantation of an embryo and placenta formation.
International Patent Publication Number WO2007033215 teaches anti-angiogenic compositions for the treatment of endometriosis and ovarian hyperstimulation.
U.S. 20040161423 teaches polymer modified PEDF for the treatment of endometriosis.